Faculty Collaboration Database

Inhibition of IFN-gamma -induced STAT1 activation by 15- deoxy-Delta 12,14-prostaglandin J2. Am J Physiol Endocrinol Metab 2003 May;284(5):E883-91

Date

01/09/2003

Pubmed ID

12517740

DOI

10.1152/ajpendo.00515.2002

Scopus ID

2-s2.0-0037404327 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

The inhibitory actions of 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2)) on inflammatory gene expression have been attributed to the ability of this prostaglandin to inhibit the activation of NF-kappaB. In this study, we have identified an additional signaling pathway sensitive to inhibition by PGJ(2). We show that PGJ(2) inhibits interferon (IFN)-gamma-stimulated phosphorylation and DNA-binding activity of STAT1. The inhibitory actions on STAT1 phosphorylation are first apparent after a 1- to 2-h incubation and are maximal after a 6-h incubation with PGJ(2), and they correlate with the expression of heat shock protein (HSP)70 in islets. In previous studies, we have correlated the inhibitory actions of PGJ(2) on inducible nitric oxide synthase (iNOS) expression and NF-kappaB activation in response to IL-1 with the increased expression of HSP70. Using overexpression and antisense depletion, we provide evidence that HSP70 does not mediate the inhibitory actions of PGJ(2) on IL-1-induced NF-kappaB or IFN-gamma-induced STAT1 activation or cytokine-stimulated iNOS expression by beta-cells. Last, we show that the inhibitory actions of a short 6-h pulse with PGJ(2) on IL-1 plus IFN-gamma-stimulated iNOS expression and NO production by beta-cells are persistent for extended periods (< or =48 h). These findings suggest that PGJ(2) inhibits multiple cytokine-signaling pathways (IL-1 and IFN-gamma), that the inhibitory actions are persistent for extended periods, and that increased HSP70 expression correlates with, but does not appear to mediate, the inhibitory actions of PGJ(2) on IL-1 and IFN-gamma signaling in beta-cells.

Author List

Weber SM, Scarim AL, Corbett JA

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cell Line
DNA-Binding Proteins
HSP70 Heat-Shock Proteins
In Vitro Techniques
Interferon-gamma
Interleukin-1
Islets of Langerhans
Male
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Prostaglandin D2
Rats
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear
STAT1 Transcription Factor
Signal Transduction
Trans-Activators
Transcription Factors